ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.554G>C (p.Arg185Thr) (rs542620119)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000169232 SCV001428425 likely pathogenic Pendred syndrome 2020-06-24 reviewed by expert panel curation The c.554G>A (p.Arg185Thr) variant in SLC26A4 was present in 0.03287% (1/3042) of South Asian alleles in gnomAD v3, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined for autosomal recessive hearing loss by the ClinGen Hearing Loss Expert Panel (PM2_Supporting; This variant has been identified in one individual with unilateral hearing loss and enlarged vestibular aqueduct with a second likely pathogenic variant in trans, as well as two probands without a second variant identified but whose phenotypes were consistent with Pendred syndrome (PM3, PP4; PMID: 24051746, 20597900, 22285650). It was also observed in one proband with limited phenotype information and no second variant identified (PMID: 31387071). Functional evidence demonstrates that the p.Arg185Thr variant may impact protein function (PS3_Supporting, PMID: 22285650, 24051746). The REVEL computational prediction tool produced a score of 0.876, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3, PS3_Supporting, PM2_Supporting, PP3, PP4.
Counsyl RCV000169232 SCV000220501 likely pathogenic Pendred syndrome 2014-07-10 criteria provided, single submitter literature only
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000214962 SCV000271454 pathogenic Rare genetic deafness 2016-01-04 criteria provided, single submitter clinical testing The p.Arg185Thr variant in SLC26A4 has been previously reported in three individ uals with hearing loss and enlarged vestibular aqueducts, including one individu al who was compound heterozygous for a second pathogenic variant in the SLC26A4 gene (Chattaraj 2013, Cirello 2012, Pourova 2010). This variant has been identif ied in 12/66734 (0.02%) of European chromosomes by the Exome Aggregation Consort ium (ExAC,; dbSNP rs542620119); however, this fre quency is low enough to be consistent with a recessive carrier frequency. In vit ro functional studies reveal that the variant results in abnormal cellular local ization of the protein and significant reduction in its normal functional activi ty (Cirello 2012, Chattaraj 2013), supporting a deleterious effect for this vari ant. In addition, computational tools and conservation analyses predict that the p.Arg185Thr variant may impact the protein. In summary, this variant meets our criteria to be classified as pathogenic.
SIB Swiss Institute of Bioinformatics RCV000677335 SCV000803604 uncertain significance Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for DFNB4, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Supporting => PS3 downgraded in strength to Supporting (PMID:22285650). PM2-Supporting => PM2 downgraded in strength to Supporting. PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:24051746).
Illumina Clinical Services Laboratory,Illumina RCV000778810 SCV000915190 likely pathogenic SLC26A4-Related Disorders 2018-08-15 criteria provided, single submitter clinical testing The SLC26A4 c.554G>C (p.Arg185Thr) variant is a missense variant that has been reported in a total of three individuals with nonsyndromic hearing loss or Pendred syndrome, including in a compound heterozygous state in one and in a heterozygous state in two (Pourova et al. 2010; Cirello et al. 2012; Chattaraj et al. 2013). One of the heterozygotes was also heterozygous for a missense variant in the FOXI1 gene, which is said to display digenic inheritance with SLC26A4. The p.Arg185Thr variant is reported at a frequency of 0.000180 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in COS-7 cells, HEK293 phoenix cells and Xenopus oocytes have demonstrated the variant results in a trafficking defect, altered maturation, and reduced function compared to wildtype. Based on the collective evidence, the p.Arg185Thr variant is classified as likely pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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